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Abstract:

This invention is directed to a method of treating Excessive daytime
Sleepiness (EDS) in a subject, comprising the step of administering a
therapeutically effective amount of a compound of Formula (I): Formula
(I) or a pharmaceutically acceptable salt or ester thereof wherein Rx is
a member selected from the group consisting of hydrogen, lower alkyl of 1
to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy
containing 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and
thioalkoxy containing 1 to 3 carbon atoms; x is an integer of 1 to 3,
with the proviso that R may be the same or different when x is 2 or 3;
R1 and R2 can be the same or different from each other and are
independently selected from the group consisting of hydrogen, lower alkyl
of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon
atoms; R1 and R2 can be joined to form a 5 to 7-membered
heterocycle substituted with a member selected from the group consisting
of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can
comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the
nitrogen atoms are not directly connected with each other or with the
oxygen atom.
##STR00001##

Claims:

1-19. (canceled)

20. A method of increasing active wakefulness or alertness in a subject,
comprising administering to the subject an effective amount of a compound
of the Formula (I): ##STR00010## or a pharmaceutically acceptable salt
thereof wherein R, R1 and R2 are hydrogen and x is 1.

21. A method of increasing active wakefulness or alertness in a subject,
comprising administering to the subject an effective amount of an
enantiomer of Formula I substantially free of other enantiomers or an
enantiomeric mixture wherein one enantiomer of Formula I predominates;
##STR00011## or a pharmaceutically acceptable salt thereof wherein R,
R1 and R2 are hydrogen and x is 1.

22. The method of claim 21, wherein the enantiomer of Formula I
predominates to the extent of about 90% or greater.

23. The method of claim 21, wherein the enantiomer of Formula I
predominates to the extent of about 98% or greater.

24. The method of claim 21, wherein the enantiomer of Formula I is an
enantiomer of Formula Ia ##STR00012## or a pharmaceutically acceptable
salt thereof.

25. The method of claim 24, wherein the enantiomer of Formula Ia is the
(R) or (D) enantiomer.

26. The method of claim 24, wherein the enantiomer of Formula Ia is the
(S) or (L) enantiomer.

27. The method of claim 24, wherein the enantiomer of Formula Ia
predominates to the extent of about 90% or greater.

28. The method of claim 24, wherein the enantiomer of Formula Ia
predominates to the extent of about 98% or greater.

29. The method of claim 21, wherein the enantiomer of Formula I
substantially free of other enantiomers is the (D) or the (R) enantiomer
of Formula Ib or an enantiomeric mixture wherein the (D) or (R)
enantiomer of Formula Ib predominates; ##STR00013## or a
pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the enantiomer of Formula Ib
predominates to the extent of about 90% or greater.

31. The method of claim 29, wherein the enantiomer of Formula Ib
predominates to the extent of about 98% or greater.

38. The method of claim 21, wherein the effective amount is from about
0.01 mg/kg/dose to about 300 mg/kg/dose.

39. The method of claim 21, wherein the effective amount is from about 1
mg/day to about 7000 mg/day.

Description:

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates generally to the fields of
pharmacology, neurology and psychiatry and to methods of treating
sleep-wake disorders. More specifically, this invention provides methods
for the use of certain carbamate compounds for the treatment of
sleep-wake disorders including excessive daytime sleepiness and
pathological somnolence.

[0003] 2. Description of Related Art

[0004] Excessive Daytime sleepiness (EDS) or pathological somnolence
refers to excessive sleepiness during the day associated with a wide
variety of disorders of sleep and wakefulness. These disorders may be
primary sleep disorders such as narcolepsy or they may be the result of
some other medical condition that has an adverse effect on sleep
patterns.

[0005] Excessive Daytime Sleepiness (EDS), is the primary complaint of
patients seen in sleep clinics, affects up to 12% of the general
population. The effects of EDS can be debilitating and even life
threatening. Patients with EDS may exhibit psychosocial distress,
decreased work or school performance, and increased risk for accidents.
The differential diagnosis of EDS requires objective assessments, such as
polysomnography and the Multiple Sleep Latency Test.

[0006] There are four major causes of EDS: (1) central nervous system
(CNS) pathologic abnormalities, such as narcolepsy and idiopathic CNS
hypersomnia; (2) qualitative or quantitative sleep deficiencies, such as
sleep apnea, obstructive sleep apnea and insufficient nocturnal sleep,
due to e.g. chronic and acute pain resulting from various medical
conditions including Parkinson's disease, urinary incontinence, multiple
sclerosis fatigue, ADHD, Alzheimer's disorder, Major Depression, Bipolar
Disorder and cardiac ischemia; (3) misalignments of the body's circadian
pacemaker with the environment (e.g. jet lag or shift work); and (4)
drugs, which can increase sleepiness either therapeutically or as a side
effect.

[0008] Fatigue and excessive sleepiness are also common symptoms of a
major depressive disorder and other mood disorders such as Bipolar
Disorder, and can be adverse side effects associated with antidepressant
drug therapy or may be residual symptoms inadequately treated with
antidepressant therapy. In addition, patients sometimes suffer sleep
related side effects associated withdrawal of antidepressant therapy.

[0009] Narcolepsy is a common cause of EDS and is a disabling neurological
disorder that was first recognized 118 years ago by Gelineau, J. B. (De
la narcolepsy, Gazette des Hopitaux Paris (1880) 53: 626-628). Narcolepsy
is a chronic disorder characterized by intermittent sleep attacks,
persistent, excessive daytime sleepiness and abnormal rapid eye movement
("REM") sleep manifestations, such as sleep-onset REM periods, cataplexy,
sleep paralysis and hypnagogic hallucinations, or both. Most patients
with narcolepsy also have disrupted nocturnal sleep.

[0011] The symptoms of narcolepsy include excessive daytime sleepiness
(EDS), hypnagogic and hypnopompic hallucinations (hallucinations during
transitions into and out of sleep, respectively), cataplexy (sudden and
reversible loss of muscle tone), sleep paralysis (an inability to move at
sleep onset or awakening) and REM sleep at sleep onset (Guilleminault, C.
1989). In narcoleptics, sleep occurs at inappropriate times and in
dangerous and embarrassing situations. Although total sleep time is near
normal, nighttime sleep is disrupted by frequent awakenings (Mitler, M.
et al., Psych Olin. N. Amer. (1987) 10:593-606).

[0012] Cataplexy, a temporary, partial or complete paralysis due to a
sudden loss of muscle tone, with unimpaired consciousness, is typically
triggered by sudden strong emotions, such as those accompanying laughter,
anger and embarrassment. In some patients, status cataplecticus, or
periods of repetitive loss of muscle tone, occurs and can last for hours
or days.

[0014] A large number of physiological and pharmacological studies have
demonstrated a close similarity between human and canine narcolepsy
(Baker, T. L. and Dement, W. C. (1985) and Nishino, S, and Mignot, E.
(1997)). These animals have all the major symptoms defining narcolepsy in
humans, including episodes of cataplexy.

[0016] Drugs used to treat cataplexy and excessive sleepiness in humans
are also effective in narcoleptics dogs (Baker and Dement, 1985).
Narcolepsy usually does not develop until adolescence in humans, but it
can be seen as early as three or as late as 45 years of age or older
(Yoss and Daly, (1960) Pediatrics 25:1025-1033; Billiard, (1985) Ann.
Clin. Res 17:220-226). The appearance of cataplexy, as a proxy variable
for the onset of narcolepsy/cataplexy, in canine narcolepsy, develops
between 4 and 24 weeks of age.

[0019] It has recently been reported that narcolepsy is linked to
dysfunction of the newly discovered hypocretin (Hcrt) (orexin) peptide
system. This report was based on a deletion in the transcripts of the
hypocretin receptor 2 (Hcrtr2) gene in narcoleptic Dobermans and
Labradors (Lin, L. et. al., Cell (1999) 97:365-376). Chemelli et al.
created Hcrt knockout mice that have abnormalities of sleep control
resembling aspects of narcolepsy (Chemelli, R. M. et al., Cell (1999)
98:437-451), as well.

[0021] Pharmacologic treatment of narcolepsy has depended on the use of
central nervous system (CNS) stimulants to increase wakefulness or to
reduce the number and severity of cataplectic attacks or hypnagogic
hallucinations. CNS stimulants can be effective in relieving the
sleepiness of narcolepsy; however, extremely high doses are necessary to
restore alertness to normal levels (Mitler, M. et al., Sleep (1993)
16:306-317). Such doses can have very dangerous side effects.

[0022] Because of these side effects, most narcoleptics use stimulants
only when absolutely needed or continuously use low-level doses not
capable of restoring normal levels of alertness. Periodic "drug holidays"
can sometimes be employed to maintain the effectiveness of stimulants
(Mitler, M. S. Sleep (1994) 17:S103-S106). Frequent naps can be effective
in permitting periods of waking alertness (Aldrich, M. S., Neurology
(1992) 42(S6):34-43). Cataplexy can sometimes be treated successfully
with tricyclic antidepressants or selective serotonin reuptake inhibitors
(SSRI's), among other medications. Both tricyclic antidepressant drugs
and SSRI's all appear to act by producing metabolites that activate
noradrenergic receptors (Nishino, S. et al., Sleep (1993) 16:706-712;
Mignot, E. et al., Psychopharmacology (1993) 113:76-82). Even with these
treatments, accidents due to sleepiness and cataplexy are common and
professional and educational attainments are significantly reduced in
narcoleptics (Broughton, W. A. and Broughton, R. J., Sleep (1994)
17:S45-S49).

[0023] Excessive daytime sleepiness (EDS) or pathological somnolence,
whether due to narcolepsy or other causes, is disabling and potentially
dangerous since it produces episodes of unintended sleep, reduced
attention, and performance errors. EDS, regardless of cause, is linked to
a variety of transportation and industrial accidents and cause decreased
job performance and considerable subjective distress. A therapeutic agent
that reduces or eliminates EDS would have important implications not only
for individual patients, but also for public health and safety.

SUMMARY OF THE INVENTION

[0024] The present invention is directed to a method of treating sleep
disorders in a subject, including excessive daytime sleepiness (EDS) or
pathological somnolence comprising, administering to a subject in need of
such treatment, a therapeutically effective amount of a compound of the
Formula (I):

##STR00002##

or a pharmaceutically acceptable salt or ester thereof wherein Rx is a
member selected from the group consisting of hydrogen, lower alkyl of 1
to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy
containing 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and
thioalkoxy containing 1 to 3 carbon atoms; x is an integer of 1 to 3,
with the proviso that R may be the same or different when x is 2 or 3;
R1 and R2 can be the same or different from each other and are
independently selected from the group consisting of hydrogen, lower alkyl
of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon
atoms; R1 and R2 can be joined to form a 5 to 7-membered
heterocycle substituted with a member selected from the group consisting
of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can
comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the
nitrogen atoms are not directly connected with each other or with the
oxygen atom.

[0025] Embodiments of the invention include a method of treating Excessive
Daytime Sleepiness (EDS) in a subject, comprising the step of
administering, to a subject in need of such treatment, a therapeutically
effective amount an enantiomer of Formula I substantially free of other
enantiomers or an enantiomeric mixture wherein one enantiomer of Formula
I predominates;

##STR00003##

or a pharmaceutically acceptable salt or ester thereof wherein Rx is a
member selected from the group consisting of hydrogen, lower alkyl of 1
to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy
containing 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and
thioalkoxy containing 1 to 3 carbon atoms; x is an integer of 1 to 3,
with the proviso that R may be the same or different when x is 2 or 3;
R1 and R2 can be the same or different from each other and are
independently selected from the group consisting of hydrogen, lower alkyl
of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon
atoms; R1 and R2 can be joined to form a 5 to 7-membered
heterocycle substituted with a member selected from the group consisting
of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can
comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the
nitrogen atoms are not directly connected with each other or with the
oxygen atom. Preferably, wherein Rx, R1 and R2 are all selected from
hydrogen. Preferably wherein one enantiomer selected from the group
consisting of Formula I predominates to the extent of about 90% or
greater.

[0026] More preferably, wherein one enantiomer selected from the group
consisting of Formula I predominates to the extent of about 98% or
greater.

[0027] Embodiments of the invention include the use, for the preparation
of a medicament for the treatment of EDS, of an enantiomer selected from
the group consisting of Formula I

##STR00004##

or a pharmaceutically acceptable salt or ester thereof wherein Rx is a
member selected from the group consisting of hydrogen, lower alkyl of 1
to 8 carbon atoms, halogen selected from F, Cl, Br and I, alkoxy
containing 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and
thioalkoxy containing 1 to 3 carbon atoms; x is an integer of 1 to 3,
with the proviso that R may be the same or different when x is 2 or 3;
R1 and R2 can be the same or different from each other and are
independently selected from the group consisting of hydrogen, lower alkyl
of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon
atoms; R1 and R2 can be joined to form a 5 to 7-membered
heterocycle substituted with a member selected from the group consisting
of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can
comprise 1 to 2 nitrogen atoms and 0 to 1 oxygen atom, wherein the
nitrogen atoms are not directly connected with each other or with the
oxygen atom.

[0028] Embodiments of the invention include a method include the use of an
enantiomer of Formula I substantially free of other enantiomers that is
the enantiomer of Formula I b (R)-(beta-amino-benzenepropyl) carbamate or
(O-carbamoyl-(D)-phenylalaninol) or an enantiomeric mixture wherein the
enantiomer of Formula Ib (R)-(beta-amino-benzenepropyl) carbamate or
(O-carbamoyl-(D)-phenylalaninol) predominates.

##STR00005##

[0029] Formula Ib (R)-(beta-amino-benzenepropyl) carbamate or
(O-carbamoyl-(D)-phenylalaninol) wherein the enantiomer of Formula Ib
(R)-(beta-amino-benzenepropyl) carbamate or
(O-carbamoyl-(D)-phenylalaninol) predominates to the extent of about 90%
or greater. More preferably, an enantiomer of Formula Ib
(R)-(beta-amino-benzenepropyl) carbamate or
(O-carbamoyl-(D)-phenylalaninol) predominates to the extent of about 98%
or greater.

[0031] The present invention is based in part on the discovery that
phenylalkylamino carbamates of Formula I have novel and unique
pharmacological properties. These compounds have been shown in both
animal models and in studies in humans to have an activating or
energizing effect. Although the precise mechanism of action is not
completely understood, it is believed that these compounds do not work by
the same mechanisms as most other known stimulant drugs in producing
their activating or energizing like effects. However, in animals,
treatment with a phenylalkylamino carbamate of Formula I at 30 mg/kg
strongly increased active wakefulness at the expense of time spent in
light sleep, deep sleep and REM sleep during the first 3 to 4 hours after
the administration. A rebound effect was seen between 4-10 hours
following administration of the compound, as an increase in time spent in
deep sleep that gradually decreased in the hours thereafter. Moreover,
the compound of Formula 1 affected other sleep-wake parameters; more
specifically it increased significantly the number of shifts from light
sleep and REM sleep into wakefulness as well as lengthened the latency of
REM sleep onset.

[0032] For these two reasons the compounds of Formula 1 are especially
suitable for use as treatment for EDS and other disorders where it is
desirable to increase the amount of time a subject spends awake. Thus,
these compounds can be safely used for this purpose to provide effective
treatment of EDS regardless of the precise etiology of the underlying
sleep disturbance.

[0033] Typically, doses of a compound of Formula I would start at 10-25
mg/day and increase in increments of about 10-25 mg./day per week until
side effects intervene or an adequate response is obtained, with a
maximum dose in the range of 500 mg/day to 2000 mg/day.

[0034] One compound of Formula I consists of the (D) enantiomer of the
structure shown below wherein Rx=R1=R2=hydrogen, in the structure shown
below the amine group is directed down from the plane of the paper,

##STR00006##

[0035] This compound is the (R) enantiomer, if named by structure and is
therefore (R)-(beta-amino-benzenepropyl) carbamate. This compound is the
dextrorotary enantiomer and can therefore also be named
O-carbamoyl-(D)-phenylalaninol and is referred to herein as the "test
compound". The two chemical names may be used interchangeably in this
specification.

[0036] This compound has been tested in numerous animal models and in
humans and has demonstrated effects including strongly increased active
wakefulness at the expense of time spent in light sleep, deep sleep and
REM sleep during the first 3 to 4 hours after the administration. In
addition, this compound increased significantly the number of shifts from
light sleep and REM sleep into wakefulness as well as lengthened the
latency of REM sleep onset. The compound also shows stimulant or
energizing effects in the Spontaneous Locomotor Activity in Mice and Rats
model.

[0037] Thus in some embodiments, the present invention is directed to a
method of preventing or reducing the severity of EDS. The method
comprising administering to a subject in need thereof a therapeutically
effective amount of a compound selected from the group consisting of
phenylalkylamino carbamates of the following Formula I:

##STR00007##

or an enantiomer, diastereomer, racemate or mixtures thereof, or a
pharmaceutically acceptable salt or ester thereof wherein;

[0038] Rx is a member selected from the group consisting of hydrogen,
lower alkyl of 1 to 8 carbon atoms, halogen selected from F, Cl, Br and
I, alkoxy containing 1 to 3 carbon atoms, nitro, hydroxy,
trifluoromethyl, and thioalkoxy containing 1 to 3 carbon atoms; x is an
integer of 1 to 3, with the proviso that R may be the same or different
when x is 2 or 3;

[0039] R1 and R2 can be the same or different from each other
and are independently selected from the group consisting of hydrogen,
lower alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7
carbon atoms; R1 and R2 can be joined to form a 5 to 7-membered
heterocycle substituted with a member selected from the group consisting
of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can
comprise 0 to 2 nitrogen atoms and 0 to 1 oxygen atoms, wherein the
nitrogen atoms are not directly connected with each other or with the
oxygen atom and the pharmaceutically acceptable salts and esters thereof.

[0040] The present method also includes the use of a compound selected
from the group consisting Formula I wherein Rx, R1 and R2 are preferably
selected from hydrogen, this is Formula Ia below;

##STR00008##

[0041] The present method also includes the use of the D enantiomer
selected from the group consisting of Formula I or an enantiomeric
mixture wherein the D enantiomer selected from the group consisting of
Formula Ia predominates wherein Rx, R1 and R2 are preferably selected
from hydrogen, this is O-carbamoyl-(D)-phenylalaninol. Formula Ib below;
(note-in Formula Ib, i.e. the D enantiomer, as shown, the amine group on
the chiral carbon is orientated into the plane of the paper)

##STR00009##

[0042] For enantiomeric mixtures wherein one enantiomer selected from the
group consisting of Formula I predominates, preferably, an enantiomer
selected from the group consisting of Formula I predominates to the
extent of about 90% or greater. More preferably, an enantiomer selected
from the group consisting of Formula I predominates to the extent of
about 98% or greater.

[0043] The compounds of Formula I can be synthesized by methods known to a
skilled artisan. The salts and esters of the compounds of Formula (I) can
be produced by treating the compound with a suitable mineral or organic
acid (HX) in suitable solvent or by other means well known to those of
skill in the art.

[0044] Details of the above reactions schemes for synthesizing compounds
of Formula (I) as well as representative examples on the preparation of
specific compounds have been described in U.S. Pat. No. 5,705,640, U.S.
Pat. No. 5,756,817, U.S. Pat. No. 5,955,499, U.S. Pat. No. 6,140,532, all
incorporated herein by reference in their entirety.

[0045] From Formula I it is evident that some of the compounds of the
invention have at least one and possibly more asymmetric carbon atoms. It
is intended that the present invention include within its scope the
stereochemically pure isomeric forms of the compounds as well as their
racemates. Stereochemically pure isomeric forms may be obtained by the
application of art known principles. Diastereoisomers may be separated by
physical separation methods such as fractional crystallization and
chromatographic techniques, and enantiomers may be separated from each
other by the selective crystallization of the diastereomeric salts with
optically active acids or bases or by chiral chromatography. Pure
stereoisomers may also be prepared synthetically from appropriate
stereochemically pure starting materials, or by using stereoselective
reactions.

[0046] During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned. This may
be achieved by means of conventional protecting groups, such as those
described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie,
Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups
in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The
protecting groups may be removed at a convenient subsequent stage using
methods known from the art.

[0047] Other embodiments of the invention include the use, for the
preparation of a medicament for the treatment of EDS, of one of the
compounds or enantiomers or enantiomeric mixtures described above or a
pharmaceutically acceptable salt or ester thereof.

[0048] All of the U.S. patents that have been mentioned above in
connection with compounds used in the present invention are incorporated
herein by reference.

DEFINITIONS

[0049] For convenience, certain terms employed in the specification,
examples, and appended claims are collected here. It is to be understood
that this invention is not limited to the particular methodology,
protocols, animal species or genera, and reagents described, as such may
vary. It is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments only, and is not
intended to limit the scope of the present invention that will be limited
only by the appended claims.

[0050] As used herein the term "Excessive Daytime Sleepiness" (EDS) shall
be used interchangeably with the term "pathological somnolence" and shall
mean a condition in which an individual feels very drowsy during the day
and has an difficult to resist urge to fall asleep, whether or not the
individual has gotten enough nighttime sleep. Excessive sleepiness is
defined as sleepiness occurring in a situation when an individual would
be expected to be awake and alert. Clinically the symptoms of EDS can be
quantified and measured in a variety of ways, including but not limited
to; the Multiple Sleep Latency Test (MSLT) (See Carskadon M A and Dement
W C, Sleep 1982; 5 Suppl 2:S67-72), the Maintenance of Wakefulness Test
(MWT) (See, Mitler M M, et al. Electroencephalogr Clin Neurophysiol,
1982; 53(6):668-61) or the Stanford Sleepiness Scale (SSS) (See, Hoddes E
et al., Psychophysiology, 1973; 10(4):431-6) (See also, Arand D et al.
Sleep, 2005; 28(1):123-144). The causes of EDS are multiple and the use
of the term EDS herein is not intended to imply any particular cause or
etiology. People with EDS frequently doze, nap, or fall asleep in
situations where they need or want to be fully awake and alert. The
diagnosis can be made when the symptoms of EDS interfere significantly
with a person's ability to concentrate and perform daily tasks and
routines such as work, family responsibilities, driving a car or
operating other hazardous machinery or general quality of life.

[0051] As used herein, the term "mental disorder" and "mental illness"
refer to those provided in the Diagnostic and Statistical Manual (DSM
IV), American Psychological Association (APA). These mental disorders
include, but are not limited to affective disorders, Major Depression and
related depressive disorders. Examples of affective disorders include
mood disorders, manic disorder, major depressive disorder and bipolar
affective disorder. Mood disorders include, but are not limited to,
depressive disorders including Major Depression with or without psychotic
features, dysthymic disorder, bipolar disorders (I and II) and
cyclothymic disorders.

[0052] As used herein the term "subject", refers to an animal, preferably
a mammal, and most preferably a human, who has been the object of
treatment, observation or experiment.

[0053] The term "therapeutically effective amount" as used herein, means
that amount of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue system, animal or human that
is being sought by a researcher, veterinarian, medical doctor or other
clinician, which includes alleviation of one or more of the signs or
symptoms of the disease or disorder being treated.

[0054] The term "prophylactically effective amount" is intended to mean
that amount of a pharmaceutical drug that will prevent or reduce the risk
of occurrence of the biological or medical event that is sought to be
prevented, in a tissue, a system, animal or human, by a researcher,
veterinarian, medical doctor or other clinician.

[0056] The terms "subject" or "patient" are used herein interchangeably
and as used herein mean any mammal, including but not limited to human
beings including a human patient or subject, to which the compositions of
the invention can be administered. The term mammals include human
patients and non-human primates, as well as experimental animals such as
rabbits, rats, and mice, and other animals.

[0057] The term "a patient in need of treatment" as used herein will refer
to any subject or patient who currently has or may develop any of the
above syndromes or disorders, including any condition or disorder in
which the subject spends an excessive amount of time in a sleep state or
unable to maintain a satisfactory degree of wakefulness during a period
of the day when wakefulness is required or desired, or any other disorder
in which the patient's present clinical condition or prognosis could
benefit from the administration of one or more compounds of Formula (I)
alone or in combination with another therapeutic intervention including
but not limited to another medication.

[0058] The term "treating" or "treatment" as used herein, refers to any
indicia of success in the prevention or amelioration of an injury,
pathology or condition, including any objective or subjective parameter
such as abatement; remission; diminishing of symptoms or making the
injury, pathology, or condition more tolerable to the patient; slowing in
the rate of degeneration or decline or worsening of the illness; making
the final point of worsening less debilitating; or improving a subject's
physical or mental well-being. The treatment or amelioration of symptoms
can be based on objective or subjective parameters; including the results
of a physical examination, sleep study, neurological examination, and/or
psychiatric evaluations. Accordingly, the term "treating" or "treatment"
includes the administration of the compounds or agents of the present
invention to provide increased alertness or decreased need for or desire
for sleep. In some instances, treatment with the compounds of the present
invention will be done in combination with other compounds to provide
increased alertness or decreased need for or desire for sleep or to
prevent, inhibit, or arrest the progression of EDS.

[0059] The term "therapeutic effect" as used herein, refers to the
effective provision of the above-described action.

[0060] The term "a therapeutically effective amount" as used herein means
a sufficient amount of one or more of the compounds of the invention to
produce a therapeutic effect, as defined above, in a subject or patient
in need of such neuroprotection treatment.

[0061] As used herein the term "concomitant administration" or
"combination administration" of a compound, therapeutic agent or known
drug with a compound of the present invention means administration of a
known medication or drug and, in addition, the one or more compounds of
the invention at such time that both the known drug and the compound will
have a therapeutic effect. In some cases this therapeutic effect will be
synergistic. Such concomitant administration can involve concurrent (i.e.
at the same time), prior, or subsequent administration of the known drug
with respect to the administration of a compound of the present
invention. A person of ordinary skill in the art, would have no
difficulty determining the appropriate timing, sequence and dosages of
administration for particular drugs and compounds of the present
invention.

[0062] In addition, in some embodiments, the compounds of this invention
will be used, either alone or in combination with each other or in
combination with one or more other therapeutic medications as described
above, or their salts or esters, for manufacturing a medicament for the
purpose of providing treatment for EDS or related conditions to a patient
or subject in need thereof.

[0063] As used herein the term "C1-C4 alkyl" refers to
substituted or unsubstituted aliphatic hydrocarbons having from 1 to 4
carbon atoms. Specifically included within the definition of "alkyl" are
those aliphatic hydrocarbons that are optionally substituted. In a
preferred embodiment of the present invention, the C1-C4 alkyl
is either unsubstituted or substituted with phenyl.

[0064] As used herein the term "test compound" (tc) or "TEST COMPOUND"
(TC) means the hydrochloride salt of (R)-(beta-amino-benzenepropyl)
carbamate which can also be named O-carbamoyl-(D)-phenylalaninol. This
compound is the (R) enantiomer, shown as Formula Ib, structurally and is
also the dextro-rotary enantiomer. Test compound is also referred to as
R228060 in the legend to Tables 14.

[0065] The term "phenyl", as used herein, whether used alone or as part of
another group, is defined as a substituted or unsubstituted aromatic
hydrocarbon ring group having 6 carbon atoms. Specifically included
within the definition of "phenyl" are those phenyl groups that are
optionally substituted. For example, in a preferred embodiment of the
present invention, the, "phenyl" group is either unsubstituted or
substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy,
amino, nitro, or cyano.

[0066] Methods are known in the art for determining therapeutically and
prophylactically effective doses for the instant pharmaceutical
composition. For example, for use as a treatment for EDS, the compounds
of this invention can be employed at a daily dose in the range of about
0.1 mg to 1000 mg usually on a regimen of 1 to 3 times per day, for an
average adult human. The effective amount, however, may be varied
depending upon the particular compound used, the mode of administration,
the strength of the preparation, the mode of administration, and the
advancement of the disease condition. In addition, factors associated
with the particular patient being treated, including patient age, weight,
diet and time of administration, will result in the need to adjust
dosages.

[0067] The compound may be administered to a subject by any conventional
route of administration, including, but not limited to, intravenous,
oral, subcutaneous, intramuscular, intradermal and parenteral. Depending
on the route of administration, compounds of Formula (I) can be
constituted into any form. For example, forms suitable for oral
administration include solid forms, such as pills, gelcaps, tablets,
caplets, capsules (each including immediate release, timed release and
sustained release formulations), granules, and powders. Forms suitable
for oral administration also include liquid forms, such as solutions,
syrups, elixirs, emulsions, and suspensions. In addition, forms useful
for parenteral administration include sterile solutions, emulsions and
suspensions.

[0068] To prepare the pharmaceutical compositions of this invention, one
or more compounds of formula (I) or salt thereof as the active ingredient
is intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques. Carriers are
necessary and inert pharmaceutical excipients, including, but not limited
to, binders, suspending agents, lubricants, flavorings, sweeteners,
preservatives, dyes, and coatings. In preparing compositions in oral
dosage form, any of the usual pharmaceutical carriers may be employed.
For example, for liquid oral preparations, suitable carriers and
additives include water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like; for solid oral preparations,
suitable carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and the
like.

[0069] For parenteral use, the carrier will usually comprise sterile water
or saline solution, though other ingredients, for example, for purposes
such as aiding solubility or for preservation, may be included.
Injectable suspensions may also be prepared, in which case appropriate
liquid carriers, suspending agents and the like may be employed.

[0070] Because of their ease in administration, tablets and capsules
represent the most advantageous oral dosage unit form, in which case
solid pharmaceutical carriers are obviously employed. If desired, tablets
may be sugar coated or enteric coated by standard techniques.
Suppositories may be prepared, in which case cocoa butter could be used
as the carrier. The tablets or pills can be coated or otherwise
compounded to provide a dosage form affording the advantage of prolonged
action. For example, the tablet or pills can comprise an inner dosage and
an outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric layer,
which serves to resist disintegration in the stomach and permits the
inner component to pass intact into the duodenum or to be delayed in
release. A variety of material can be used for such enteric layers or
coatings, such materials including a number of polymeric acids with such
materials as shellac, cetyl alcohol and cellulose acetate.

[0071] Active drug may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules are
coupled. Active drug may also be coupled with soluble polymers as
targetable drug carriers. Such polymers can include
polyvinyl-pyrrolidone, pyran copolymer,
polyhydroxy-propyl-methacrylamide-phenol,
polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues. Furthermore, active drug may be
coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid, polyglycolic
acid, copolymers of polylactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross linked or amphipathic
block copolymers of hydrogels.

[0073] Alternatively, the composition may be presented in a form suitable
for once-weekly or once-monthly administration; for example, an insoluble
salt of the active compound, such as the decanoate salt, may be adapted
to provide a depot preparation for intramuscular injection.

[0074] The pharmaceutical compositions herein will contain, per dosage
unit, e.g., tablet, capsule, powder, injection, teaspoonful, suppository
and the like, an amount of the active ingredient necessary to deliver an
effective dose as described above. For example, the pharmaceutical
compositions herein can contain, per unit dosage unit, from about 10 to
about 1000 mg of the active ingredient. Preferably, the range is from
about 25 to about 200 mg of the active ingredient.

[0075] In some embodiments of the present invention carbamate compounds
suitable for use in the practice of this invention will be administered
either singly or concomitantly with at least one or more other compounds
or therapeutic agents, e.g., with other agents that tend to increase
arousal or alertness. In these embodiments, the present invention
provides methods to treat or prevent EDS in a patient. The method
includes the step of; administering to a patient in need of treatment, an
effective amount of one of the carbamate compounds disclosed herein in
combination with an effective amount of one or more other compounds or
therapeutic agents that have the ability to provide advantageous combined
effects such as the ability to augment the activating effects of the
compounds of the invention.

[0076] It is understood that substituents and substitution patterns on the
compounds of the present invention can be selected by one of ordinary
skill in the art to provide compounds that are chemically stable and that
can be readily synthesized by techniques known in the art as well as the
methods provided herein.

[0077] The present invention includes the use of isolated enantiomers of
Formula I. In one preferred embodiment, a pharmaceutical composition
comprising the isolated S-enantiomer of Formula I is used to provide
treatment to a subject. In another preferred embodiment, a pharmaceutical
composition comprising the isolated R-enantiomer of Formula I is used to
provide treatment to a subject.

[0078] The present invention also includes the use of mixtures of
enantiomers of Formula I. In one aspect of the present invention, one
enantiomer will predominate. An enantiomer that predominates in the
mixture is one that is present in the mixture in an amount greater than
any of the other enantiomers present in the mixture, e.g., in an amount
greater than 50%. In one aspect, one enantiomer will predominate to the
extent of 90% or to the extent of 91%, 92%, 93%, 94%, 95%, 96%, 97% or
98% or greater. In one preferred embodiment, the enantiomer that
predominates in a composition comprising a compound of Formula I is the
S-enantiomer of Formula I.

[0079] The present invention provides methods of using enantiomers and
enantiomeric mixtures of compounds represented by Formula I. A carbamate
enantiomer of Formula I contains an asymmetric chiral carbon at the
benzylic position, which is the second aliphatic carbon adjacent to the
phenyl ring.

[0080] An enantiomer that is isolated is one that is substantially free of
the corresponding enantiomer. Thus, an isolated enantiomer refers to a
compound that is separated via separation techniques or prepared free of
the corresponding enantiomer.

[0081] The term "substantially free," as used herein, means that the
compound is made up of a significantly greater proportion of one
enantiomer. In preferred embodiments, the compound includes at least
about 90% by weight of a preferred enantiomer. In other embodiments of
the invention, the compound includes at least about 99% by weight of a
preferred enantiomer. Preferred enantiomers can be isolated from racemic
mixtures by any method known to those skilled in the art, including high
performance liquid chromatography (HPLC) and the formation and
crystallization of chiral salts, or preferred enantiomers can be prepared
by methods described herein.

Carbamate Compounds as Pharmaceuticals:

[0082] The present invention provides racemic mixtures, enantiomeric
mixtures and isolated enantiomers of Formula I as pharmaceuticals. The
carbamate compounds are formulated as pharmaceuticals to provide
treatment for EDS and related conditions in a subject.

[0083] In general, the carbamate compounds of the present invention can be
administered as pharmaceutical compositions by any method known in the
art for administering therapeutic drugs including oral, buccal, topical,
systemic (e.g., transdermal, intranasal, or by suppository), or
parenteral (e.g., intramuscular, subcutaneous, or intravenous injection.)
Administration of the compounds directly to the nervous system can
include, for example, administration to intracerebral, intraventricular,
intracerebealventricar, intrathecal, intracisternal, intraspinal or
peri-spinal routes of administration by delivery via intracranial or
intravertebral needles or catheters with or without pump devices.

[0084] Compositions can take the form of tablets, pills, capsules,
semisolids, powders, sustained release formulations, solutions,
suspensions, emulsions, syrups, elixirs, aerosols, or any other
appropriate compositions; and comprise at least one compound of this
invention in combination with at least one pharmaceutically acceptable
excipient. Suitable excipients are well known to persons of ordinary
skill in the art, and they, and the methods of formulating the
compositions, can be found in such standard references as Alfonso A R:
Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,
Easton Pa., 1985, the disclosure of which is incorporated herein by
reference in its entirety and for all purposes. Suitable liquid carriers,
especially for injectable solutions, include water, aqueous saline
solution, aqueous dextrose solution, and glycols.

[0085] The carbamate compounds can be provided as aqueous suspensions.
Aqueous suspensions of the invention can contain a carbamate compound in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients can include, for example, a suspending
agent, such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, and dispersing or wetting agents such as a
naturally occurring phosphatide (e.g., lecithin), a condensation product
of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),
a condensation product of ethylene oxide with a long chain aliphatic
alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of
ethylene oxide with a partial ester derived from a fatty acid and a
hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty acid
and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).

[0086] The aqueous suspension can also contain one or more preservatives
such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents,
one or more flavoring agents, and one or more sweetening agents, such as
sucrose, aspartame or saccharin. Formulations can be adjusted for
osmolarity.

[0087] Oil suspensions for use in the present methods can be formulated by
suspending a carbamate compound in a vegetable oil, such as arachis oil,
olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin; or a mixture of these. The oil suspensions can contain a
thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
Sweetening agents can be added to provide a palatable oral preparation,
such as glycerol, sorbitol or sucrose. These formulations can be
preserved by the addition of an antioxidant such as ascorbic acid. As an
example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther,
281:93-102, 1997. The pharmaceutical formulations of the invention can
also be in the form of oil-in-water emulsions. The oily phase can be a
vegetable oil or a mineral oil, described above, or a mixture of these.

[0088] Suitable emulsifying agents include naturally occurring gums, such
as gum acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty acids
and hexitol anhydrides, such as sorbitan mono-oleate, and condensation
products of these partial esters with ethylene oxide, such as
polyoxyethylene sorbitan mono-oleate. The emulsion can also contain
sweetening agents and flavoring agents, as in the formulation of syrups
and elixirs. Such formulations can also contain a demulcent, a
preservative, or a coloring agent.

[0089] The compound of choice, alone or in combination with other suitable
components can be made into aerosol formulations (i.e., they can be
"nebulized") to be administered via inhalation. Aerosol formulations can
be placed into pressurized acceptable propellants, such as
dichlorodifluoromethane, propane, nitrogen, and the like.

[0090] Formulations of the present invention suitable for parenteral
administration, such as, for example, by intraarticular (in the joints),
intravenous, intramuscular, intradermal, intraperitoneal, and
subcutaneous routes, can include aqueous and non-aqueous, isotonic
sterile injection solutions, which can contain antioxidants, buffers,
bacteriostats, and solutes that render the formulation isotonic with the
blood of the intended recipient, and aqueous and non-aqueous sterile
suspensions that can include suspending agents, solubilizers, thickening
agents, stabilizers, and preservatives. Among the acceptable vehicles and
solvents that can be employed are water and Ringer's solution, an
isotonic sodium chloride. In addition, sterile fixed oils can
conventionally be employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid can likewise be
used in the preparation of injectables. These solutions are sterile and
generally free of undesirable matter.

[0091] Where the compounds are sufficiently soluble they can be dissolved
directly in normal saline with or without the use of suitable organic
solvents, such as propylene glycol or polyethylene glycol. Dispersions of
the finely divided compounds can be made-up in aqueous starch or sodium
carboxymethyl cellulose solution, or in suitable oil, such as arachis
oil. These formulations can be sterilized by conventional, well-known
sterilization techniques. The formulations can contain pharmaceutically
acceptable auxiliary substances as required to approximate physiological
conditions such as pH adjusting and buffering agents, toxicity adjusting
agents, e.g., sodium acetate, sodium chloride, potassium chloride,
calcium chloride, sodium lactate and the like.

[0092] The concentration of a carbamate compound in these formulations can
vary widely, and will be selected primarily based on fluid volumes,
viscosities, body weight, and the like, in accordance with the particular
mode of administration selected and the patient's needs. For IV
administration, the formulation can be a sterile injectable preparation,
such as a sterile injectable aqueous or oleaginous suspension. This
suspension can be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents. The sterile
injectable preparation can also be a sterile injectable solution or
suspension in a nontoxic parenterally acceptable diluents or solvent,
such as a solution of 1,3-butanediol. The formulations of commends can be
presented in unit-dose or multi-dose sealed containers, such as ampoules
and vials. Injection solutions and suspensions can be prepared from
sterile powders, granules, and tablets of the kind previously described.

[0093] A carbamate compound suitable for use in the practice of this
invention can be and is preferably administered orally. The amount of a
compound of the present invention in the composition can vary widely
depending on the type of composition, size of a unit dosage, kind of
excipients, and other factors well known to those of ordinary skill in
the art. In general, the final composition can comprise, for example,
from 0.000001 percent by weight (% w) to 50% w of the carbamate compound,
preferably 0.00001% w to 25% w, with the remainder being the excipient or
excipients.

[0094] Pharmaceutical formulations for oral administration can be
formulated using pharmaceutically acceptable carriers well known in the
art in dosages suitable for oral administration. Such carriers enable the
pharmaceutical formulations to be formulated in unit dosage forms as
tablets, pills, powder, dragees, capsules, liquids, lozenges, gels,
syrups, slurries, suspensions, etc. suitable for ingestion by the
patient.

[0095] Formulations suitable for oral administration can consist of (a)
liquid solutions, such as an effective amount of the pharmaceutical
formulation suspended in a diluents, such as water, saline or PEG 400;
(b) capsules, sachets or tablets, each containing a predetermined amount
of the active ingredient, as liquids, solids, granules or gelatin; (c)
suspensions in an appropriate liquid; and (d) suitable emulsions.

[0096] Pharmaceutical preparations for oral use can be obtained through
combination of the compounds of the present invention with a solid
excipient, optionally grinding a resulting mixture, and processing the
mixture of granules, after adding suitable additional compounds, if
desired, to obtain tablets or dragee cores. Suitable solid excipients are
carbohydrate or protein fillers and include, but are not limited to
sugars, including lactose, sucrose, mannitol, or sorbitol; starch from
corn, wheat, rice, potato, or other plants; cellulose such as methyl
cellulose, hydroxymethyl cellulose, hydroxypropylmethyl-cellulose or
sodium carboxymethylcellulose; and gums including arabic and tragacanth;
as well as proteins such as gelatin and collagen.

[0097] If desired, disintegrating or solubilizing agents can be added,
such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a
salt thereof, such as sodium alginate. Tablet forms can include one or
more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn
starch, potato starch, microcrystalline cellulose, gelatin, colloidal
silicon dioxide, talc, magnesium stearate, stearic acid, and other
excipients, colorants, fillers, binders, diluents, buffering agents,
moistening agents, preservatives, flavoring agents, dyes, disintegrating
agents, and pharmaceutically compatible carriers. Lozenge forms can
comprise the active ingredient in a flavor, e.g., sucrose, as well as
pastilles comprising the active ingredient in an inert base, such as
gelatin and glycerin or sucrose and acacia emulsions, gels, and the like
containing, in addition to the active ingredient, carriers known in the
art.

[0098] The compounds of the present invention can also be administered in
the form of suppositories for rectal administration of the drug. These
formulations can be prepared by mixing the drug with a suitable
non-irritating excipient that is solid at ordinary temperatures but
liquid at the rectal temperatures and will therefore melt in the rectum
to release the drug. Such materials are cocoa butter and polyethylene
glycols.

[0101] Encapsulating materials can also be employed with the compounds of
the present invention and the term "composition" can include the active
ingredient in combination with an encapsulating material as a
formulation, with or without other carriers. For example, the compounds
of the present invention can also be delivered as microspheres for slow
release in the body. In one embodiment, microspheres can be administered
via intradermal injection of drug (e.g., mifepristone)-containing
microspheres, which slowly release, subcutaneously (see Rao, J. Biomater
Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel
formulations (see, e.g., Gao, Pharm. Res. 12:857-863, 1995); or, as
microspheres for oral administration (see, e.g., Eyles, J. Pharm.
Pharmacol, 49:669-674, 1997). Both transdermal and intradermal routes
afford constant delivery for weeks or months. Cachets can also be used in
the delivery of the compounds of the present invention.

[0102] In another embodiment, the compounds of the present invention can
be delivered by the use of liposomes which fuse with the cellular
membrane or are endocytosed, i.e., by employing ligands attached to the
liposome that bind to surface membrane protein receptors of the cell
resulting in endocytosis. The active drug can also be administered in the
form of liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles and multilamellar vesicles. Liposomes can be
formed from a variety of phospholipids, such as cholesterol, stearylamine
or phosphatidylcholines.

[0104] The pharmaceutical formulations of the invention can be provided as
a salt and can be formed with many acids, including but not limited to
hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
Salts tend to be more soluble in aqueous or other protonic solvents that
are the corresponding free base forms. In other cases, the preferred
preparation can be a lyophilized powder which can contain, for example,
any or all of the following: 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7%
mannitol, at a pH range of 4.5 to 5.5, that is combined with buffer prior
to use.

[0105] Pharmaceutically acceptable salts and esters refers to salts and
esters that are pharmaceutically acceptable and have the desired
pharmacological properties. Such salts include salts that may be formed
where acidic protons present in the compounds are capable of reacting
with inorganic or organic bases. Suitable inorganic salts include those
formed with the alkali metals, e.g. sodium and potassium, magnesium,
calcium, and aluminum. Suitable organic salts include those formed with
organic bases such as the amine bases, e.g. ethanolamine, diethanolamine,
triethanolamine, tromethamine, N methylglucamine, and the like.
Pharmaceutically acceptable salts can also include acid addition salts
formed from the reaction of amine moieties in the parent compound with
inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic
acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and
arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic
acid). Pharmaceutically acceptable esters include esters formed from
carboxy, sulfonyloxy, and phosphonoxy groups present in the compounds.
When there are two acidic groups present, a pharmaceutically acceptable
salt or ester may be a mono-acid-mono-salt or ester or a di-salt or
ester; and similarly where there are more than two acidic groups present,
some or all of such groups can be salified or esterified.

[0106] Compounds named in this invention can be present in unsalified or
unesterified form, or in salified and/or esterified form, and the naming
of such compounds is intended to include both the original (unsalified
and unesterified) compound and its pharmaceutically acceptable salts and
esters. The present invention includes pharmaceutically acceptable salt
and ester forms of Formula (I). More than one crystal form of an
enantiomer of Formula I can exist and as such are also included in the
present invention.

[0107] A pharmaceutical composition of the invention can optionally
contain, in addition to a carbamate compound, at least one other
therapeutic agent useful in the treatment of EDS. For example the
carbamate compounds of Formula I can be combined physically with other
activating or stimulant compounds in fixed dose combinations to simplify
their administration.

[0108] Methods of formulating pharmaceutical compositions have been
described in numerous publications such as Pharmaceutical Dosage Forms:
Tablets. Second Edition. Revised and Expanded. Volumes 1-3, edited by
Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications.
Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms:
Disperse Systems. Volumes 1-2, edited by Lieberman et al; published by
Marcel Dekker, Inc, the disclosure of which are herein incorporated by
reference in their entireties and for all purposes.

[0109] The pharmaceutical compositions are generally formulated as
sterile, substantially isotonic and in full compliance with all Good
Manufacturing Practice (GMP) regulations of the U.S. Food and Drug
Administration.

Dosage Regimens

[0110] The present invention provides methods of providing treatment for
EDS and related conditions in a mammal using carbamate compounds. The
amount of the carbamate compound necessary to provide treatment for EDS
and related conditions is defined as a therapeutically or a
pharmaceutically effective dose. The dosage schedule and amounts
effective for this use, i.e., the dosing or dosage regimen will depend on
a variety of factors including the stage of the disease, the patient's
physical status, age and the like. In calculating the dosage regimen for
a patient, the mode of administration is also taken into account.

[0111] A person of ordinary skill in the art will be able without undue
experimentation, having regard to that skill and this disclosure, to
determine a therapeutically effective amount of a particular substituted
carbamate compound for practice of this invention (see, e.g., Lieberman,
Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, 1999, The art,
Science and Technology of Pharmaceutical Compounding; and Pickar, 1999,
Dosage Calculations). A therapeutically effective dose is also one in
which any toxic or detrimental side effects of the active agent is
outweighed in clinical terms by therapeutically beneficial effects. It is
to be further noted that for each particular subject, specific dosage
regimens should be evaluated and adjusted over time according to the
individual need and professional judgment of the person administering or
supervising the administration of the compounds.

[0112] For treatment purposes, the compositions or compounds disclosed
herein can be administered to the subject in a single bolus delivery, via
continuous delivery over an extended time period, or in a repeated
administration protocol (e.g., by an hourly, daily or weekly, repeated
administration protocol). The pharmaceutical formulations of the present
invention can be administered, for example, one or more times daily, 3
times per week, or weekly. In one embodiment of the present invention,
the pharmaceutical formulations of the present invention are orally
administered once or twice daily.

[0113] In this context, a therapeutically effective dosage of the
biologically active agent(s) can include repeated doses within a
prolonged treatment regimen that will yield clinically significant
results to provide treatment for EDS and related conditions.
Determination of effective dosages in this context is typically based on
animal model studies followed up by human clinical trials and is guided
by determining effective dosages and administration protocols that
significantly reduce the occurrence or severity of targeted exposure
symptoms or conditions in the subject. Suitable models in this regard
include, for example, murine, rat, porcine, feline, non-human primate,
and other accepted animal model subjects known in the art. Alternatively,
effective dosages can be determined using in vitro models (e.g.,
immunologic and histopathologic assays).

[0114] Using such models, only ordinary calculations and adjustments are
typically required to determine an appropriate concentration and dose to
administer a therapeutically effective amount of the biologically active
agent(s) (e.g., amounts that are intranasally effective, transdermally
effective, intravenously effective, or intramuscularly effective to
elicit a desired response).

[0115] In an exemplary embodiment of the present invention, unit dosage
forms of the compounds are prepared for standard administration regimens.
In this way, the composition can be subdivided readily into smaller doses
at the physician's direction. For example, unit dosages can be made up in
packeted powders, vials or ampoules and preferably in capsule or tablet
form.

[0116] The active compound present in these unit dosage forms of the
composition can be present in an amount of, for example, from about 10
mg. to about one gram or more, for single or multiple daily
administration, according to the particular need of the patient. By
initiating the treatment regimen with a minimal daily dose of about one
gram, the blood levels of the carbamate compounds can be used to
determine whether a larger or smaller dose is indicated.

[0117] Effective administration of the carbamate compounds of this
invention can be administered, for example, at an oral or parenteral dose
of from about 0.01 mg/kg/dose to about 150 mg/kg/dose. Preferably,
administration will be from about 0.1/mg/kg/dose to about 25 mg/kg/dose,
more preferably from about 0.2 to about 18 mg/kg/dose. Therefore, the
therapeutically effective amount of the active ingredient contained per
dosage unit as described herein can be, for example, from about 1 mg/day
to about 7000 mg/day for a subject having, for example, an average weight
of 70 kg.

[0118] The methods of this invention also provide for kits for use in
providing treatment for EDS and related conditions. After a
pharmaceutical composition comprising one or more carbamate compounds of
this invention, with the possible addition of one or more other compounds
of therapeutic benefit, has been formulated in a suitable carrier, it can
be placed in an appropriate container and labeled for providing treatment
for EDS and related conditions. Additionally, another pharmaceutical
comprising at least one other therapeutic agent can be placed in the
container as well and labeled for treatment of the indicated disease.
Such labeling can include, for example, instructions concerning the
amount, frequency and method of administration of each pharmaceutical.

[0119] Although the foregoing invention has been described in detail by
way of example for purposes of clarity of understanding, it will be
apparent to the artisan that certain changes and modifications are
comprehended by the disclosure and may be practiced without undue
experimentation within the scope of the appended claims, which are
presented by way of illustration not limitation. The following examples
are provided to illustrate specific aspects of the invention and are not
meant to be limitations.

Example

Study Purpose

[0120] This study was undertaken to determine the effect of the (D) or (R)
enantiomer of a phenylalkylamino carbamate of Formula I, specifically
O-carbamoyl-(D)-phenylalaninol which can also be named
(R)-(beta-amino-benzenepropyl) carbamate shown above as Formula Ib,
referred to herein as "TEST COMPOUND" on the sleep-wake organization in
rats after acute administration of test compound, in direct comparison to
amphetamine and cocaine.

[0121] In order to characterize the profile of activity of TEST COMPOUND
in sleep-wake organization in rats, animals were chronically implanted
with electrodes for recording the cortical electroencephalogram,
electrical neck muscle activity, and ocular movements, while whole body
movement levels were simultaneously registered. Secondly, effects were
compared with those obtained with two reference psychostimulant drugs,
cocaine and amphetamine. Changes in sleep-wake organization can be
reliably detected on the basis of such polysomnographic recordings.
Subsequent analysis of the pattern of changes has been validated to
predict the class of psychotropic agents to which the compound under
investigation resembles best. (See, Ruigt, G S et al. (1993)
Neuropsychobiology; 28(3):138-153)

Materials and Methods

Animals

[0122] The experiments were carried out on male adult Sprague Dawley rats,
supplied by Harlan (Borchen, Germany) weighing 240-260 g at time of
surgery. Animals were housed in full-view Plexiglas cages
(25×33×18 cm) that fit to IVC-racks (individually ventilated
cages) located in a sound attenuated chamber. Rats were provided with a
micro-chip for identification purposes and maintained under controlled
environmental conditions throughout the study: 22±2° C. ambient
temperature, relative humidity at 60%, 12:12 light-dark cycle (lights on
from 12:00 hrs to 00:00 hrs; light intensity ˜100 lux) with
standard laboratory food chow and tap water available ad libitum. The
institutional animal care and use committee approved all animal
procedures.

Surgery

[0123] Under isoflurane inhalation anesthesia, the rats were mounted in a
stereotaxic apparatus. The oval area of the scalp was removed, and the
uncovered skull was cleared of the periosteum. Three small cavities were
drilled into the cranial bone without perforating the dura to receive 3
fixing stainless steel screws (diameter 1 mm) for polygraphic recording
of frontal and parietal electroencephalogram (EEG). Two electrodes were
placed stereotaxically on each side of the sagittal suture (AP+2 mm, L-2
mm; and AP-6 mm, L 3 mm from Bregma, while the third (reference)
electrode was screwed over the cerebellum. The incisor bar was -5 mm
under the centre of the ear bar, according to the stereotactic atlas of
Paxinos G. & Watson C. The Rat Brain in Stereotaxic Coordinates, Academic
Press, San Diego, Calif., U.S.A. (1998).

[0124] For the recording of the electro-oculogram (EOG) and electromyogram
(EMG), stainless steel wires were placed in pen-orbital, and inserted
into nuckal muscle, respectively. Electrodes (stainless steel wire,
7N51465T5TLT, 51/46 Teflon Bilaney, Germany) were connected to a pin
(Future Electronics: 0672-2-15-15-30-27-10-0) with a small insert (track
pins; Dataflex: TRP-1558-0000) were fitted into a 8 holes connector.
Finally, the electrodes were fixed with dental cement to the cranium. The
animals were housed individually and were allowed to recover for at least
one week.

Sleep Recording Procedure and Pharmacological Test

[0125] Ten days after surgery, the animals were habituated for two weeks
to the recording procedure in their home cages. The rats were connected
at regular intervals with a cable to a rotating swivel allowing free
movements while EEG, EOG and EMG activities were monitored.

[0126] Only rats that complied with the required criteria were used at
time of testing i.e. weight of animals 300-700 g, good polygraphical
signal quality, a wash out period of at least 14 days in case of subject
reuse, and no failure in two successive test sessions. For each compound,
two EEG recording sessions were performed in 32 operated animals that
were randomly assigned to 4 treatment conditions (n=8 rats per
condition).

[0127] The first recording session started at 14:00 hrs and lasted 16
hours after administration of saline (n=32 rats). The second recording
session was performed for the same duration following administration of
saline and different doses of TEST COMPOUND (1, 3 and 10 mg/kg), cocaine
(3, 10 and 30 mg/kg i.p.), or amphetamine (3, 10, 30 mg/kg i.p.). All
compounds were dissolved in saline and administered in a volume of
10-ml/kg-body weight. An equivalent volume of saline was administered in
control conditions. The EEG, EOG, EMG signals and body movement
activities were monitored for 16 hours. The acquisition of data was
performed with a sample rate of 200 Hz. All signals were passed via a
bipolar recorder system (Embla) developed by MedCare (Iceland) to a
computer and managed by a software package (Somnologica, MedCare,
Iceland) which turns the computer into a polygraphic workstation for
signal recording.

[0131] The scores were synchronized in time with the EEG signal and the
system calculated automatically different sleep-wake parameters such as
amount of time spent in each state, number and duration of episodes in
each vigilance state, latencies for ISWS, dSWS and REMS and the number of
shifts from one state to another one. For each sleep state, the latency
was defined as the time between the beginning of the recording and the
appearance of the first sleep period lasting at least 30 seconds.

Statistical Analysis

[0132] Time spent in each vigilance state (AW, PW, ISWS, dSWS, IS and
REMS) were expressed in percentage of the recording period. A statistical
analysis of the obtained data was carried out by a non parametric
analysis of variance per 30-min periods followed by a
Wilcoxon-Mann-Whitney rank sum tests in comparisons with the control
group.

Effects of TEST COMPOUND

[0133] The administration of TEST COMPOUND produced significant changes in
the distribution of sleep-wake states.

[0134] A slight modification of the sleep-wake architecture was observed
throughout the 16 hours recording period following the administration of
the lowest dose of the compound (3 mg/kg i.p.). An increase in total
light sleep (+26%, p<0.05) and an increased drive to wakefulness from
light sleep as well as deep sleep (+46%, p<0.001; +15%, p<0.05;
respectively) were observed indicating aspects of sleep fragmentation
following this dose of the compound (p<0.05) (see Table 4).

[0135] At the dose of 10 mg/kg i.p. TEST COMPOUND produced changes in the
sleep wake organization associated with a significant increase in total
duration of light sleep (+24%, p<0.05) and a significant increase in
shifts from REM sleep towards active wakefulness. (+16%, p<0.05) (See
Tables 2 and 4). During the first 90 minutes of the recording period a
significant decrease in deep sleep duration in favor of increase in time
spent in active wakefulness was observed, (p<0.05).

[0136] At the highest dose (30 mg/kg i.p.) test compound produced
pronounced changes in the distribution of the sleep-wake cycle. A marked
increase of the total time spent in the active wakefulness (+19%,
p<0.05), a reduction of total time spent in passive wakefulness (-29%,
p<0.05), in light sleep (-20%, p<0.05) as well as REM sleep (-25%,
p<0.05) over the course of the 16-h post-injection period of the
registration (see Table 2). In addition, when compared to total sleep
time, TEST COMPOUND induced an increase in time spent in deep sleep and
decreased time in REM sleep (p<0.05) (see Table 4).

[0137] A significant enhancement of active wakefulness was observed during
the first 3 hours following the administration of TEST COMPOUND
(p<0.01). Concomitantly, a large reduction in the time spent in sleep
e.g. light sleep (p<0.01), deep sleep (p<0.01) and REM sleep
(p<0.01), followed by a rebound effect particularly an increase in
deep sleep after 3 hours following the administration of TEST COMPOUND.
The latter effect lasted about 7 hours during the light period of the
recording. It should be noted that the onset of activity of TEST COMPOUND
was almost immediate namely around the first 30 minutes following
administration.

[0138] The large increase in total time spent in active wakefulness and
the reduction in passive wakefulness, light sleep and REM sleep were due
to an increase (+19%, p<0.05), and a decrease (-30%, p<0.05; -23%,
p<0.05; -24%, p<0.01) in the number of epochs of these sleep-wake
stages, respectively. However, the mean durations of these sleep wake
states were not modified.

[0139] As depicted (see Table 4) TEST COMPOUND at 30 mg/kg produced an
increase in the number of shifts from light sleep and REM sleep towards
wakefulness (p<0.05) and thus suggests indications of sleep
fragmentation. Examination of sleep latencies revealed significant
changes following TEST COMPOUND administration (see Table 1). TEST
COMPOUND at 10 and 30 mg/kg produced a significant lengthening of the
latencies of REM sleep onset.

Effects of Cocaine

[0140] The major modifications in sleep architecture following the
administration of cocaine were observed with the highest dose tested i.e.
a decrease in total time spent in REM sleep (-18%) sleep namely in favour
of an increase in total duration of active wakefulness (+14%) throughout
16 hours recording following the treatment. Additionally, no effects of
cocaine at the different doses tested were observed on total sleep time
as well as on the number of shifts from sleep toward wakefulness.

[0142] The increased amount of active wakefulness following the
administration of cocaine at the dose of 10 mg/kg resulted from an
increase in the number of epochs (0.5 h: +111%, p<0.001; 1 h: +500%,
p<0.001; 1.5 hr: +312%, p<0.001; 2 h: +119%, p<0.001; 2.5 hr:
+166%, p<0.05; 3 hr: +77%, p<0.001) while the mean duration of this
state was not affected.

[0143] The reduction of time spent in light sleep and deep sleep during
the first 2 hours of the recording period was due to a decrease in number
of epochs of these states (0.5 h: -100% and 100%, p<0.001; 1 hr: -99%
and -100%, p<0.001; 1.5 h: -87% and -100%, p<0.001; 2 hr: -22% and
-38%, p<0.05, respectively). Likewise, the decrease in time duration
spent in REM sleep during the first 3 hours derived from a reduction in
number of epochs of this state (0.5 hr, 1 hr, 1.5 hr: each -100%,
p<0.001; 2 hr: -87%, p<0.001; -2.5 hr; -47%, p<0.00; 3 hr: -78%,
p<0.001), respectively.

[0145] During the total recording period of 16 hours, amphetamine at 1, 3,
and 10 mg/kg produced significant changes in sleep-wake organization.
Amphetamine dose-dependently increased the total time spent in active
wakefulness (+27%, p<0.05; +47%, p<0.001; +66%, p<0.001), deep
(rebound) sleep (+73%, p<0.05; +91%, p<0.05; +66%, p<0.001), and
decreased the total time spent in light sleep (-35%, p<0.05; -49%,
p<0.05; -51%, p<0.001), and REM sleep (-4%; -22%, p<0.05; -41%,
p<0.001), respectively (See Table 2). Moreover, when compared to
vehicle, amphetamine at 3 and 10 mg/kg proportionally reduced total sleep
time (p<0.001) and time spent in light sleep, while the compound
increased the proportion of deep sleep compared to total time spent
asleep (p<0.05) (see Table 3). The large increase in active
wakefulness and deep sleep following the administration of 1, 3, and 10
mg/kg of amphetamine resulted from an increase in the number of active
wake epochs (+27%, p<0.05; +47%, p<0.001; +66%, p<0.001;
respectively) and deep sleep epochs (+73%, p<0.001; +91%, p<0.001;
+66%, p<0.001). While the mean duration of active wake was not
modified for different doses of the compound, the mean duration of deep
sleep stage was reduced following 3 and 10 mg/kg of the compound (-19%,
p<0.05; -30%, p<0.05).

[0146] The reduction in light SWS and REM sleep total time after the
administration of 1, 3, and 10 mg/kg of amphetamine were due to a
decrease in the number of light sleep epochs (-35%, p<0.05; -49%,
p<0.001; -51%, p<0.001; respectively), and REM sleep epochs (-4%;
-22%, p<0.05; -41%, p<0.001; respectively. The mean duration of REM
sleep stage were decreased (-16%, p<0.05; -23%, p<0.05; -36%,
p<0.05; respectively), while this parameter was not significantly
modified for light sleep. Amphetamine enhanced active wakefulness in a
clearly dose-dependent fashion during a period of 3, 4, and 6 hours (1,
3, and 10 mg/kg respectively; p<0.05;). Concomitantly, a dose
dependent reduction in light, deep and REM sleep durations as observed
over a period of 3, 4, 6 hours (p<0.05, respectively) following
administration.

[0147] Amphetamine had a biphasic effect on the time spent in deep sleep
stage i.e. it was largely reduced during 3-6 hours following the
injection and then increased as a likely rebound effect during the light
period of the recording.

[0148] As indicated in Table 1, amphetamine significantly affected sleep
parameters by lengthening the onset latencies of sleep states
(p<0.001).

Results:

[0149] Minor changes in vigilance states were observed after the
administration of TEST COMPOUND at the dose of 3 and 10 mg/kg. However,
treatment with TEST COMPOUND at 30 mg/kg strongly increased active
wakefulness at the expense of time spent in light sleep, deep sleep and
REM sleep during the first 3 to 4 hours after the administration. A
rebound effect was seen between 4-10 hours following administration of
the compound, as an increase in time spent in deep sleep that gradually
decreased in the hours thereafter. Moreover, TEST COMPOUND affected other
sleep-wake parameters; more specifically it increased significantly the
number of shifts from light sleep and REM sleep into wakefulness as well
as lengthened the latency of REM sleep onset.

[0150] Cocaine administered at the dose of 1 and 3 mg/kg only slightly
affected the sleep-wake organization. In contrast, cocaine at 10 mg/kg
significantly enhanced active wakefulness and reduced slow wave sleep and
REM sleep during the first 3 to 4 hours following injection of the
compound. All sleep latencies were increased. Amphetamine
dose-dependently increased wakefulness and reduced all sleep states
during 3 to 8 hours following administration. A clear dose-dependent
rebound effect was observed for deep. Additionally, the latencies of all
sleep states were significantly increased.

CONCLUSIONS

[0151] The present findings show that almost immediately after
intraperitoneal injection TEST COMPOUND was centrally active for at least
4 hours with a peak in effect around 2 hours post administration. Only
minor effects on sleep-wake architecture were observed at the lowest dose
tested of 3 mg/kg. Changes in the sleep parameters were observed with the
middle (10 mg/kg) and more specifically with the higher dose of 30 mg/kg
tested. The modifications of the sleep-wake distribution which were most
obvious during the first 3 hours of the registration period were
characterized by an large increase of time spent in active wakefulness,
while time spent in passive wakefulness, light sleep, deep sleep and REM
sleep was reduced. Interestingly, TEST COMPOUND produced a rebound effect
of recovery deep sleep associated with a marked increase in time spent in
this state up to 7 hours.

[0152] The effects observed in this comparative study clearly suggest that
TEST COMPOUND at 30 mg/kg has psychostimulant-like proprieties at the
beginning of the administration while a consequently following increase
in sleep propensity as shown by deep sleep enhancement point towards a
potential indirect effect on sleep homeostasis.

[0153] The overall TEST COMPOUND profile of effects at 30 mg/kg was
remarkably similar to the profile observed following the administration
of amphetamine at the lowest dose tested of 1 mg/kg, both in terms of
effect pattern, size and duration.

[0154] Therefore, TEST COMPOUND showed, in rats, central activity
immediately after injection as expressed in changes sleep-wake
architecture with a functional peak in effect around 2 hrs after i.p.
administration. The findings show that TEST COMPOUND produced a biphasic
effect i.e. an Initial increase in wakefulness and reduction in sleep was
followed by an increase in (deep) sleep, most likely a rebound effect,
which lasted for 4-10 hours. These findings resemble closely the effects
on sleep-wake architecture observed following administration of
psychostimulant drugs; most specifically amphetamine at the lowest dose
tested (i.e. at 1 mg/kg i.p.). Consequently, outcomes suggest that TEST
COMPOUND is likely to have stimulant-like proprieties immediately after
administration.

[0155] All references cited herein are incorporated herein by reference in
their entirety and for all purposes to the same extent as if each
individual publication or patent or patent application was specifically
and individually indicated to be incorporated by reference in its
entirety for all purposes.

[0156] The discussion of references herein is intended merely to summarize
the assertions made by their authors and no admission is made that any
reference constitutes prior art. Applicants reserve the right to
challenge the accuracy and pertinence of the cited references.

[0157] The present invention is not to be limited in terms of the
particular embodiments described in this application, which are intended
as single illustrations of individual aspects of the invention. Many
modifications and variations of this invention can be made without
departing from its spirit and scope, as will be apparent to those skilled
in the art. Functionally equivalent methods and apparatus within the
scope of the invention, in addition to those enumerated herein will be
apparent to those skilled in the art from the foregoing description and
accompanying drawings. Such modifications and variations are intended to
fall within the scope of the appended claims. The present invention is to
be limited only by the terms of the appended claims, along with the full
scope of equivalents to which such claims are entitled.